Phenanthrenyl-butadienols

ABSTRACT

Phenanthrenyl-butadienols, e.g., 2-(2-phenanthrenyl)-3,4pentadien-2-ol and their preparation are described. The compounds are useful as anti-inflammatories.

Umted States Patent 1 [111 3,875,244

Anderson Apr. 1, 1975 PHENANTHRENYL-BUTADIENOLS [56] References Cited [75] inventor: Paul L. Anderson, Dover, NJ. FOREIGN PATENTS OR APPLICATIONS 2,258,349 6/1973 Germany 260/618 R [73] Assignee: Sandoz-Wander, lnc., Hanover, NJ. OTHER PUBLICATIONS ec Oelin et 3]- Chem- Abstracts VOI. 77, l (1972).

[211 App]. No.: 429,403

Primary Eraminef-Joseph E. Evans Assistant E.\aminerD. B. Springer [52] 260/618 260/247] 260/293'83 Attorney, Agent, or Firm-Gerald D. Sharkin; Richard 260/326.87, 260/345.9, 260/347.8, E Vila. Frederick H weinfeldt 260/456 P, 260/456 R, 260/618 D,

260/618 F, 260/567.6 M, 424/343 [57] ABSTRACT 51 lm. Cl. C071! 33/06 Phenanthrenyl-butadienbls, e.g.. -p yh- [58] Field of Search 260/618 F 3,4-pentadien-2-ol and their preparation are described. The

compounds are useful as antiinflammatories.

3 Claims, N0 Drawings R and R independently represent alkyl having I to 4 carbon atoms; unsubstituted cycloalkyl having 5 to 6 ring carbons, i.e., cyelopentyl or cyelohexyl; or together, with N, represent a heterocyclic ringhaving 5 to 7 members selected from the group consisting of unsubstituted pyrrolidino, piperidino, homopiperidino, morpholino, and their alkyl substituted derivatives containing from I to 3 alkyl groups of l to 4 carbon atoms;

R represents alkyl having I to 4 carbon atoms, e.g., methyl, ethyl, propyl or butyl Including isomeric forms where they exist, although the unbranched alkyls are preferred, especially methyl, and

X is an anion derived from a mineral acid or an organic sulfonic acid, provided that X is not fluoro, e.g., iodo or methylsulfonyl.

Compounds Ila can be prepared by quaternizing a compound of the formula V:

on 1, l v v A- cl: CECCH2N wherein A, R, .R and R are as defined above, with a compound of the formula VI:

RX VI wherein R and X are as defined above. The qu aternization can be carried out in the conventional manner, e.g., in a suitable solvent such as acetone, at a temperature of from 2() to +3()C., neither OII wherein A and R are as defined above, and L is tetrahydrofuran-2-yloxy, tetrahydropyran-Z- yloxy or 4-methoxy-tetrahydropyran-4-yloxy can be prepared by reacting a compound of the formula VII VII wherein A and R are defined above, with Grignard reagent formed by treating a compound of the formula VIII:

HC=CCH --L VIII wherein ,c.g., methane sulfonyloxy, ethanesulfonyloxy, 3-

A c- CEC CH2 L"' IIe wherein A and R are as defined above, and

L is fluoro, chloro or bromo can be prepared by reacting a compound of the for mula IX:

wherein A and R are as defined above with the appropriate halide selected from the group of thionyl chloride or bromide, phosphorus pentachloride or bromide and hydrocarbon sulfonyl fluorides, e.g., benzyl sulfonyl fluoride, tosyl fluoride and mesyl lluoride, in an organic medium such as hexane, benzene or dimethoxyglycol. For the chlorination and bromination a tertiary amine base, such as pyridine, is included in the reaction mixture and the reaction temperature is about 0 to 20C. For the fluorination the reaction temperature is 0 to about l5()C.

Compounds of formula II in which L is iodo are conveniently prepared by reacting corresponding compounds of formula He in which L"' is chloro, with sodium iodide in acetone, the reaction being carried out in conventional manner for replacing a chloro with an iodo.

The compounds of formula II in which L is a sulfonyloxy radical are conipounds'of formula Ild:

IId

wherein A and R are as defined above, and

L" is a sulfonyloxy radical which may be either alkylsulfonyloxy in which the alkyl group may be substituted, e.g., halo, or unsubstituted and contain from I to as many as 16 or more, preferably l to 6 carbon atoms,

chloropropanesulfonyloxy, or I hexadecanesulfonyloxy; or arylsulfonyloxy in which the aryl group is phenyl, na'phthyl'or substituted phenyl, which may have from I to 3 s ubstituents independently selected from the group consisting of alkyl of l to 6 car- PHENANTHRENYL-BUTADIENOLS This invention relates to 2,3-butadienols, and more particularly, to phenanthrenyl-butadienols, as well as to pharmaceutical compositions containing such compounds and to the pharmaceutical use of such compounds.

The compounds of this invention may be conveniently represented by the formula I:

I or:

wherein R is a hydrogen atom, methyl or ethyl, preferably methyl.

Compounds l are obtainable by reducing with a complex metal hydride, a corresponding alkynol compound of the formula ll, (process a):

L is either a) a quaternary ammonium radical; b) an ether selected from the group consisting oftetrahydrofuran-Z-yloxyz tetrahydropyran-Z-yloxy or 4- methoxy-tetrahydropyran-4-yloxy: c) halo having an atomic weight of from about [9 to I27, e.g., fluoro, chloro, bromo or iodo; or d) a sulfonyloxy radical.

The complex hydride reducing agents may be of the formula lllu or Ill/2:

Z Z l l M Z T H IIIa, or T H IIIb wherein u T is aluminum, gallium or boron,and

Z, Z and Z are, independently, a hydrogen atom,

alkyl of l to 6 carbon atoms, alkoxy of l, to 6 carbon atoms; or alkoxyalkoxy having from 2 to 6 total carbon atoms:

Z and Z are, independently, hydrogen or alkyl of lto 6 carbon atoms: and

M is an alkali or alkaline earth metal, such as lithium,

' sodium, potassium, calcium or magnesium. Exemplary of such complex hydrides are lithium aluminum hydride, sodium dihydrobis (Z-methoxyethoxy) aluminate, sodium diethyl aluminum dihydride, lithium borohydride, lithium gallium hydride, magnesium aluminum hydride, lithium diisobutylmethyl aluminum hydride, lithium trimethoxy aluminum hydride, diethyl aluminum hydride and diborane, preferably lithium aluminum hydride or sodium dihydrobis (2- methoxycthoxy) aluminate.

The complex hydrides (lllu and lllh) are either known and may be prepared by methods described in the literature or where not known may be prepared by methods analogous to those for preparing the known compounds. Many of the complex hydrides are commercially available.

Process a) should be carried out in a medium which is not detrimental to the reaction, such as in an aprotic organic solvent, e.g., an ether such as diethyl ether, tetrahydrofuran or dioxane, an aromatic medium, such as benzene, toluene or pyridine or a saturated aliphatic hydrocarbon, such as pentane, hexane or octane. The medium may be a mixture or a single material. The reaction may, for example, be carried out at about 4() to +l2()C., e.g., at the boiling point of the medium. However, temperatures of from about 1 0 to +5()C. are preferred. While the higher temperatures result in a faster reaction rate, reactions carried out at lower temperatures tend to give purer products. The reaction product (a Compound I) may be recovered by conventional means, e.g., by carefully adding a small amount of water or aqueous solution, c.g., aqueous ammonium chloride, or sodium hydroxide to the reaction mixture, filtering off the inorganic by-products or hydrolysis products of the hydride ion source, and then separating the Compound 1 product from the organic phase by such means as precipitation, extraction, crystallization, chromatography or liquid-liquid extraction. As will be appreciated by those skilled in the art, it is preferred to exclude moisture from the reaction, e.g., by use of anhydrous solvents and conditions. The reaction may be advantageously carried out in an inert atmosphere, e.g., under nitrogen gas.

The compounds of formula ll in which L is a quaternary ammonium radical are compounds of formula llu:

A and R are as defined above; and L is the radical:

wherein bon atoms, alkoxy of l to 6 carbon atoms, halo and nitro.

pound of the formula lX above with an appropriate alkylsulfonyl chloride, such as methanesulfonyl chloride, 3-chloropropanesulfonyl chloride or I I- hexadecanesulfonyl chloride or an arylsulfonyl chloride, such as benzensulfonyl chloride, 4- tolucnesulfonyl chloride or 2-naphthalenesulfonyl chloride. This reaction is conveniently carried out in pyridine at or about room temperature.

The compounds offormula lX used in the production of compounds llc' and lld can be prepared by conventional hydrolysis of a compound of formula III), such as with a mineral or organic acid.

The compounds of formula V used in the preparation of Compounds Ila, above, can be prepared by reacting a compound of formula Vll above with a compound of formula Xl:

wherein R and R are as defined above, with lithium metal at a temperature of 0 to 50C. in a suitable solvent such as ethylene diamine.

The compounds of formula V can also be prepared by a process (b) which involves reacting a compound of formula Xll:

XII

wherein A and R are as defined above, with a compound of formula Xlll:

liO m C11 N XIII wherein R and R are as defined above.

In process b), a compound of formula Xll is reacted with a compound of formula Xlll at a temperature of to 50C. preferably at room temperature, in the presence of an inert solvent, and in the presence of Compounds lld can be prepared by reacting a commono-valent coinage metalion, c.g., copper ion, as cutalyst, preferably cuprous chloride or; cuprous oxide, although salts and the like of other coinage metals, i.e., silver and gold (I), can like-wise be used. The compounds of formula XII can beiprepared by reacting a compound of formula Vll above in a solvent such as dimethylacetamide or dimethylsulfoxide with a suitable acetylene reagent, such as sodium or lithium acetylide conveniently at room temperature.

The compounds of formulae XIII and XIV used in the above-identified preparations of compounds V are known or can be produced from known materials by conventional techniques, and many are commercially available.

The compounds of formula (I) are useful because they possess pharmacological activity in animals In particular, the compounds (I) are useful as antiinflammatory agents as indicated by the Carrageenan induced edema test on rats (oral administration at l to 200 mg/kg). For such use, the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants as may be necessary, and administered orally in such forms as tablets and capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. The dosage administered will, of course, vary depending upon the compounds used and the mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 milligram to about 250 milligrams per kilo gram, e.g., from about 1 milligram to about milligrams per kilogram of body weight, preferably given in divided doses 2 to 4 times a day, or in sustained release form. For most mammals, the administration of from about milligrams to about 3000 milligrams, e.g., from about milligrams to about2000-milligrams, of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about 25 milligrams to about 1500 milli grams, e.g., from about 40 milligrams to about 1000 milligrams, of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

For the above usage, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for manufacture or pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatablle preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic' acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (leci- Ingredient Weight in Milligrams 'l'ahlet Capsule Capsule 2-( l-phenanthrenyl )-3.4- 50 5t) 30 pentadien-Z-ol 'lragaeanth l Lactose 1975 150 Corn Starch Z 'lalcum l5 Magnesium Stearate 2.5 Pol \'eth \'lene (ilyeol 300 In the following example which is illustrative of the invention, temperatures are in degrees centigrade, and room temperature is to C., unless indicated otherwise.

EXAMPLE 2-( Z-phenanthrenyl )-3 ,4-pentadien-2-ol (IJH c CH e CH2 I Step A. To a Grignard mixture prepared from 3.92 g of magnesium and 19.1 g of bromoethane in a total of 225 ml. dry tetrahydrofuran is added 22 g of 3-(2'-tetrahydropyranyloxy)-propyne. After the addition is completed, IO g of Z-acetyl-phenanthrene dissolved in (10 ml. of dry tetrahydrofuran is added dropwise. The mixture is stirred l8 hours at room temperature, then poured into 300 ml. of a cold saturated ammonium chloride solution. The organic phase is separated. The aqueous phase is extracted with benzene and the henzene extract is combined with the organic phase. The combined organic phase is washed twice with 200 ml. portions of a lN sodium hydroxide solution. The solution is dried over anhydrous magnesium sulfate, filtered from drying agent, and evaporated under reduced pressure to yield a dark oil. The oil is chromatographed on a silica gel G column using benzenepentane l:l as the elutant to obtain 2-( Z-phenanthrenyl )-5-( 2 tetrahydropyranyloxy)-3-pentyn-2-ol. Step B. To 14.7 g of the product from Step A, dissolved in ml. dry tetrahydrofuran, 42 ml. of a 0.98 molar ether solution of lithium aluminum hydride is added dropwise. The solution is stirred 18 hours at room tem perature, then 5 ml. of a 2071 sodium hydroxide solution is added slowly. A large amount of anhydrous sodium sulfate is added. The drying agent is filtered off and the filtrate is evaporated under reduced pressure to yield an oil. The oil is chromatographed on a silica gel G column using benzene-pentane l :l as an elutant to obtain refined 2-(Z-phenanthrenyl)-3,4-pentadien-2- ol, m.p. 788lC.

Repeating the procedure of this example but using in place of the Z-aeetylphenanthrene used in Step A, an.

approximately equivalent amount of:

a. l-(Z-phenanthrenyl)-propan-l-one; or b. Z-phenanthrene aldehyde;

there is similarly obtained:

a. 3-(Z-phenanthrenyl)-4,5-hexadien-3-ol; or b. 1(2-phenanthrenyl )-2,3-butadienl -ol. What is claimed is:

l. A compound of the formula:

wherein R is a hydrogen atom, methyl or ethyl.

2. A compound of claim 1 in which R is methyl. 3. A compound of claim 1 in which R is a hydrogen atom or ethyl.

=l l l l 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 in which R is methyl.
 3. A compound of claim 1 in which R is a hydrogen atom or ethyl. 